Androgen receptor and chemokine receptors 4 and 7 form a signaling axis to regulate CXCL12-dependent cellular motility

BMC Cancer

Jordy J Hsiao²  Brandon H Ng²  Melinda M Smits²  Jiahui Wang²  Rohini J Jasavala⁴  Harryl D Martinez²  Jinhee Lee²  Jhullian J Alston²  Hiroaki Misonou³  James S Trimmer¹  Michael E Wright² 

[1] Department of Neurobiology, Physiology and Behavior and Department of Physiology and Membrane Biology, University of California Davis, School of Medicine, One Shields Avenue, Davis 95616, California, USA

[2] Department of Molecular Physiology & Biophysics, The University of Iowa, Carver College of Medicine, 51 Newton Road, Iowa City 52242, Iowa, USA

[3] Graduate School of Brain Science, Doshisha University, Kyoto, Japan

[4] Department of Pharmacology, Davis Genome Center, University of California Davis School of Medicine, One Shields Avenue, Davis 95616, California, USA

关键词: Prostate cancer;    Cell motility;    CXCR7;    CXCR4;    Androgen receptor;   

Others  :  1161226
DOI  :  10.1186/s12885-015-1201-5

 received in 2014-09-24, accepted in 2015-03-17,  发布年份 2015

【 摘 要 】

Background

Identifying cellular signaling pathways that become corrupted in the presence of androgens that increase the metastatic potential of organ-confined tumor cells is critical to devising strategies capable of attenuating the metastatic progression of hormone-naïve, organ-confined tumors. In localized prostate cancers, gene fusions that place ETS-family transcription factors under the control of androgens drive gene expression programs that increase the invasiveness of organ-confined tumor cells. C-X-C chemokine receptor type 4 (CXCR4) is a downstream target of ERG, whose upregulation in prostate-tumor cells contributes to their migration from the prostate gland. Recent evidence suggests that CXCR4-mediated proliferation and metastasis of tumor cells is regulated by CXCR7 through its scavenging of chemokine CXCL12. However, the role of androgens in regulating CXCR4-mediated motility with respect to CXCR7 function in prostate-cancer cells remains unclear.

Methods

Immunocytochemistry, western blot, and affinity-purification analyses were used to study how androgens influenced the expression, subcellular localization, and function of CXCR7, CXCR4, and androgen receptor (AR) in LNCaP prostate-tumor cells. Moreover, luciferase assays and quantitative polymerase chain reaction (qPCR) were used to study how chemokines CXCL11 and CXCL12 regulate androgen-regulated genes (ARGs) in LNCaP prostate-tumor cells. Lastly, cell motility assays were carried out to determine how androgens influenced CXCR4-dependent motility through CXCL12.

Results

Here we show that, in the LNCaP prostate-tumor cell line, androgens coordinate the expression of CXCR4 and CXCR7, thereby promoting CXCL12/CXCR4-mediated cell motility. RNA interference experiments revealed functional interactions between AR and CXCR7 in these cells. Co-localization and affinity-purification experiments support a physical interaction between AR and CXCR7 in LNCaP cells. Unexpectedly, CXCR7 resided in the nuclear compartment and modulated AR-mediated transcription. Moreover, androgen-mediated cell motility correlated positively with the co-localization of CXCR4 and CXCR7 receptors, suggesting that cell migration may be linked to functional CXCR4/CXCR7 heterodimers. Lastly, CXCL12-mediated cell motility was CXCR7-dependent, with CXCR7 expression required for optimal expression of CXCR4 protein.

Conclusions

Overall, our results suggest that inhibition of CXCR7 function might decrease the metastatic potential of organ-confined prostate cancers.

【 授权许可】

   
2015 Hsiao et al.; licensee BioMed Central.

【 图 表 】

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